The long term goals of this research are to determine the molecular basis for tropism and trafficking of Epstein-Barr virus (EBV) in infected individuals and to evaluate its relevance to disease. EBV is a human herpesvirus that is a chronic intermittent inhabitant of the oral cavity of almost one hundred per cent of the adult population worldwide and is a potential threat to all those infected. It causes oral hairy leukoplakia, a proliferative lesion of the oral epithelium in AIDS patients, the latest in a diverse list of virus associated pathologies. EBV induces infectious mononucleosis, it is involved in the pathogenesis of nasopharyngeal carcinoma, immunoblastic lymphoma and Burkitt's lymphoma, and it may play a role in the etiology of Sjogren's syndrome and Hodgkin's disease. With the exception of infectious mononucleosis, all of these conditions result from loss of control of chronic rather than acute infection with EBV. The virus infects two cell types. It establishes primarily latent infections in B lymphocytes and replicates productively in epithelial cells of the parotid gland and the oro and nasopharynx. The source of virus in saliva is thought to be epithelium which is continuously reinfected by small numbers of circulating lymphocytes that shift from latent to productive infection. Little is known about trafficking between the two cell types, but the tropism of virus or virus-producing lymphocytes for epithelium is expected to be influenced by glycoproteins that are found in the virion envelope and in the membrane of the cell. The immediate objective of this proposal is to take advantage of new reagents and techniques to investigate the roles of two recently identified virus glycoproteins in repeated infection of the oro and nasopharynx. The first two specific aims are to construct virus that is deleted for the expression of the glycoproteins, and to compare the in vitro phenotypes of wild type and mutant viruses. The third and fourth aims are to derive an animal model to study EBV infection by establishing vascularized human epithelium in the peritoneal cavities of immunodeficient C.B-17 scid/scid mice, and to examine the trafficking into engrafted tissue of virus and lymphocytes that are infected with EBV. The final aim is to compare the abilities of wild type and mutant viruses to traffick between lymphoid and epithelial cells in the animal model. Understanding these dynamics of infection with EBV is viewed as critical to resolving its effects in the immunodeficient host.